Journal
NEUROIMAGE-CLINICAL
Volume 35, Issue -, Pages -Publisher
ELSEVIER SCI LTD
DOI: 10.1016/j.nicl.2022.103099
Keywords
Multiple sclerosis; Magnetic resonance imaging; Neuro filament; Disconnectome mapping; Longitudinal
Categories
Funding
- European Commission (ERACO-SYSMED ERA-Net program, Sys4MS project) [:43]
- European Union?s Horizon 2020 Research and Innovation program (ERC StG) [802998]
- Instituto de Salud Carlos III, Spain [AC1500052]
- Italian Ministry of Health [WFR-PER-2013-02361136]
- German Ministry of Science [For?derkennzeichen: 031L0083B]
- Norwegian Research Council [257955]
- Biogen Norway [2018-02532]
- Swedish Research Council [ALFGBG-715986]
- County Councils [818521]
- European Research Council (ERC) under the European Union?s Horizon 2020 research and innovation programme [681712]
- European Research Council [ALFGBG-720931]
- Swedish State Support for Clinical Research [201809-2016862]
- Alzheimer Drug Discovery Foundation (ADDF) , USA [ADSF-21-831376-C, ADSF-21-831381-C, (#ADSF-21-831377-C)]
- AD Strategic Fund [FO2019-0228]
- Alzheimer?s Association [860197]
- Olav Thon Foundation
- Erling-Persson Family Foundation
- Stiftelsen for?Gamla Tja?narinnor
- Hja?rnfonden, Sweden
- European Union?s Horizon 2020 research and innovation programme under the Marie Sk?odowska-Curie
- UK Dementia Research Institute at UCL
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Connectivity-based approaches can be more sensitive in detecting axonal damage in patients with multiple sclerosis. This study used individual brain disconnectome mapping to investigate the associations between imaging-based brain network aberrations and levels of serum neurofilament light chain (NfL) as a biomarker for neuroaxonal injury.
Background and Objectives: Connectivity-based approaches incorporating the distribution and magnitude of the extended brain network aberrations caused by lesions may offer higher sensitivity for axonal damage in patients with multiple sclerosis (MS) than conventional lesion characteristics. Using individual brain disconnectome mapping, we tested the longitudinal associations between putative imaging-based brain network aberrations and levels of serum neurofilament light chain (NfL) as a neuroaxonal injury biomarker. Methods: MS patients (n = 312, mean age 42.9 years, 71 % female) and healthy controls (HC) (n = 59, mean age 39.9 years, 78 % female) were prospectively enrolled at four European MS centres, and reassessed after two years (MS, n = 242; HC, n = 30). Post-processing of 3 Tesla (3 T) MRI data was performed at one centre using a harmonized pipeline, and disconnectome maps were calculated using BCBtoolkit based on individual lesion maps. Global disconnectivity (GD) was defined as the average disconnectome probability in each patient's white matter. Serum NfL concentrations were measured by single molecule array (Simoa). Robust linear mixed models (rLMM) with GD or T2-lesion volume (T2LV) as dependent variables, patient as a random factor, serum NfL, age, sex, timepoint for visit, diagnosis, treatment, and center as fixed factors were run. Results: rLMM revealed significant associations between GD and serum NfL (t = 2.94, p = 0.003), age (t = 4.21, p = 2.5 x 10(-5)), and longitudinal changes in NfL (t =-2.29, p = 0.02), but not for sex (t = 0.63, p = 0.53) or treatments (t = 0.80-0.83, p = 0.41-0.42). Voxel-wise analyses revealed significant associations between dysconnectivity in cerebellar and brainstem regions and serum NfL (t = 7.03, p < 0.001). Discussion: In our prospective multi-site MS cohort, rLMMs demonstrated that the extent of global and regional brain disconnectivity is sensitive to a systemic biomarker of axonal damage, serum NfL, in patients with MS. These findings provide a neuroaxonal correlate of advanced disconnectome mapping and provide a platform for further investigations of the functional and potential clinical relevance of brain disconnectome mapping in patients with brain disorders.
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